miR-379 deletion ameliorates features of diabetic kidney disease by enhancing adaptive mitophagy via FIS1

• Published in: Communications biology Vol. 4; no. 1; p. 30
• Main Authors: Kato, Mitsuo, Abdollahi, Maryam, Tunduguru, Ragadeepthi, Tsark, Walter, Chen, Zhuo, Wu, Xiwei, Wang, Jinhui, Chen, Zhen Bouman, Lin, Feng-Mao, Lanting, Linda, Wang, Mei, Huss, Janice, Fueger, Patrick T, Chan, David, Natarajan, Rama
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/89; 14/28; 14/63; 38/39; 38/91; 631/61/17/1511; 692/4022/1585/104/1586; 96; 96/109; 96/95; Albuminuria - metabolism; Animals; Argonaute 2 protein; Biology; Biomedical and Life Sciences; Body weight; Body weight loss; Clear cell-type renal cell carcinoma; CRISPR; Diabetes; Diabetes mellitus; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Endoplasmic reticulum; Extracellular Matrix - metabolism; Glomerular Basement Membrane - pathology; Hybrids; Kidney diseases; Life Sciences; Mesangial cells; Mesangial Cells - metabolism; Mice; Mice, Knockout; MicroRNAs; miRNA; Mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - metabolism; Mitophagy; Oxidative stress; Phenotypes; Proteins; Therapeutic targets; Thioredoxin
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-020-01516-w

Diabetic kidney disease (DKD) is a major complication of diabetes. Expression of members of the microRNA (miRNA) miR-379 cluster is increased in DKD. miR-379, the most upstream 5′-miRNA in the cluster, functions in endoplasmic reticulum (ER) stress by targeting EDEM3. However, the in vivo functions of miR-379 remain unclear. We created miR-379 knockout (KO) mice using CRISPR-Cas9 nickase and dual guide RNA technique and characterized their phenotype in diabetes. We screened for miR-379 targets in renal mesangial cells from WT vs. miR-379KO mice using AGO2-immunopreciptation and CLASH (cross-linking, ligation, sequencing hybrids) and identified the redox protein thioredoxin and mitochondrial fission-1 protein. miR-379KO mice were protected from features of DKD as well as body weight loss associated with mitochondrial dysfunction, ER- and oxidative stress. These results reveal a role for miR-379 in DKD and metabolic processes via reducing adaptive mitophagy. Strategies targeting miR-379 could offer therapeutic options for DKD. Kato, Abdollahi et al. identify a redox protein thioredoxin and mitochondrial fission-1 (FIS1) protein as miR-379 targets in mouse kidney. They find that miR-379 knockout mice are protected from diabetic kidney disease by enhancing mitophagy via FIS1, suggesting miR-379 as a potential therapeutic target for diabetic kidney disease.